ENCePP Guide on Methodological Standards in Pharmacoepidemiology

10.2. Vaccine safety and effectiveness

10.2.1. Vaccine safety

10.2.1.1. General aspects

Specific aspects of vaccines to be considered in pharmacovigilance and pharmacoepidemiology have been highlighted in several documents. The Report of the CIOMS/WHO Working Group on Definition and Application of Terms for Vaccine Pharmacovigilance (2012) emphasises that characteristics of the vaccine and the vaccinated population, settings and circumstances of vaccine administration and data analysis issues are worthy of special attention during vaccine safety monitoring. It also provides definitions and explanatory notes for the terms ‘vaccine pharmacovigilance’, ‘vaccination failure’ and ‘adverse event following immunisation (AEFI)’. Recommendations on vaccine-specific aspects of the EU pharmacovigilance system, including on risk management, signal detection and post-authorisation safety studies (PASS) are presented in the Module P.I: Vaccines for prophylaxis against infectious diseases of the Good pharmacovigilance practices (GVP).

Methods for vaccine pharmacovigilance have been developed by the Brighton Collaboration, which provides resources to facilitate and harmonise collection, analysis and presentation of vaccine safety data, including case definitions, an electronic tool to help the classification of reported signs and symptoms, template protocols and guidelines. The CIOMS Guide to Active Vaccine Safety Surveillance (2017) describes the process of determining whether active vaccine safety surveillance is necessary, more specifically in the context of resource-limited countries, and, if so, of choosing the best type of active safety surveillance and considering key implementation issues. Module 4 (Surveillance) of the e-learning training course Vaccine Safety Basics of the World Health Organization (WHO) describes phamacovigilance principles, causality assessment procedures, surveillance systems and factors influencing the risk-benefit balance of vaccines. In particular, in contrast to the use of other medicines, vaccines are often used in healthy people and it is not only important to identify possible risks but also to emphasize safety if it does exist. For example a systematic review on influenza vaccination in pregnancy and the risk of congenital anomalies in newborns did not find an association, adding to the evidence base of influenza vaccination in pregnancy (Maternal Influenza Vaccination and Risk for Congenital Malformations: A Systematic Review and Meta-analysis. Obstet Gynecol 2015;126(5):1075-84.).

10.2.1.3. Signal refinement

When prompt decision-making about a safety concern is required and there is insufficient time to review individual cases, the GVP Module P.I: Vaccines for prophylaxis against infectious diseases suggests the conduct of observed vs. expected (O/E) analyses for signal validation and preliminary signal evaluation. The module discusses key requirements of O/E analyses: the observed number of cases detected in a passive or active surveillance systems, near real-time exposure data, appropriately stratified background incidence rates (to calculate the expected number of cases) and sensitivity analyses around these measures.

Simple ‘snapshot’ O/E analyses are easy to perform but may not be appropriate for continuous monitoring due to inflation of type 1 error rates when multiple tests are performed. Safety monitoring of Influenza A/H1N1 pandemic vaccines in EudraVigilance (Vaccine 2011;29(26):4378-87) illustrates that simple ‘snapshot’ O/E analyses are also affected by uncertainties regarding the numbers of vaccinated individuals and age-specific background incidence rates.

10.2.1.4. Hypothesis testing studies

Traditional study designs such as cohort and case-control studies may be difficult to implement for vaccines where studies involve populations with high vaccine coverage rates, an appropriate unvaccinated group is lacking or adequate information on covariates at the individual level is not available. Frequent sources of confounding to be considered are socioeconomic status, underlying health status and other factors influencing the probability of being vaccinated. Control without separate controls: evaluation of vaccine safety using case-only methods (Vaccine 2004; 22(15-16):2064-70) describes and illustrates epidemiological methods that are useful in such situations. They are mostly case-only design described in section 5.3.2 of the Guide.:

The case-crossover design was primarily developed to investigate the association between a vaccine and an adverse event. In this design, control information for each case is based on own past exposure experience and a person can ‘crossover’ between two or more exposure levels. It is a retrospective design that requires the strong assumption that the underlying probability of vaccination should be the same in all defined time intervals, but this is unlikely to hold for paediatric vaccines administered according to strict schedules or for seasonally administered vaccines.

The self-controlled case series (SCCS) design can be both prospective and retrospective and aims to estimate a relative incidence, which compares the incidence of adverse events within periods of hypothesised excess risk due to exposure with incidence during all other times.

The study Control without separate controls: evaluation of vaccine safety using case-only methods (Vaccine 2004; 22(15-16):2064-70) concludes that properly designed and analysed epidemiological studies using only cases, especially the SCCS method, may provide stronger evidence than large cohort studies as they control completely for fixed individual-level confounders (such as demographics, genetics and social deprivation) and typically have similar, sometimes better, power. Three factors are however critical in making optimal use of such methods: access to good data on cases, computerised vaccination records with the ability to link them to cases and availability of appropriate analysis techniques.

Several studies on vaccines have compared traditional and case-only study designs:

Epidemiological designs for vaccine safety assessment: methods and pitfalls (Biologicals 2012;40(5):389-92) used three study designs (cohort, case-control and self-controlled case series) to illustrate the issues that may arise when designing an epidemiological study, such as understanding the vaccine safety question, case definition and finding, limitations of data sources, uncontrolled confounding, and pitfalls that apply to the individual designs.

Comparison of epidemiologic methods for active surveillance of vaccine safety (Vaccine 2008; 26(26):3341-3345) performed a simulation study to compare four designs (matched-cohort, vaccinated-only (risk interval) cohort, case-control and self-controlled case series) in the context of vaccine safety surveillance. The cohort study design allowed for the most rapid signal detection, the least false-positive error and highest statistical power in performing sequential analysis. The authors highlight, however, that the chief limitation of this simulation is the exclusion of confounding effects and the lack of chart review, which is a time and resource intensive requirement.

10.2.1.6. Studies on vaccine safety in special populations

The article Vaccine safety in special populations (Hum Vaccin 2011;7(2):269-71) highlights common methodological issues that may arise in evaluating vaccine safety in special populations, especially infants and children who often differ in important ways from healthy individuals and change rapidly during the first few years of life, and elderly patients.

10.2.2. Vaccine effectiveness

10.2.2.1. Definitions

Vaccine effects and impact of vaccination programmes in post-licensure studies (Vaccine 2013;31(48):5634-42) reviews and delineates, among the various evaluations of vaccine intervention, what applies to the effectiveness of vaccine and to the impact of vaccination programmes, proposes epidemiological measures of public health impact, describes relevant methods to measure these effects and discusses the assumptions and potential biases involved.

10.2.2.2. Traditional cohort and case-control studies

Generic protocols for retrospective case-control studies and retrospective cohort studies to assess the effectiveness of rotavirus vaccination in EU Member States based on computerised databases were published by the European Centre for Disease Prevention and Control (ECDC). They describe the information that should be collected by country and region in vaccine effectiveness studies and the data sources that may be available to identify virus-related outcomes a vaccine is intended to avert, including hospital registers, computerised primary care databases, specific surveillance systems (i.e. laboratory surveillance, hospital surveillance, primary care surveillance) and laboratory registers. Based on a meta-analysis comprising 49 cohort studies and 10 case-control studies, Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review (Lancet 2005;366(9492):1165-74) highlights the heterogeneity of outcomes and study populations included in such studies and the high likelihood of selection bias.

10.2.2.3. Screening method

The screening method estimates vaccine effectiveness by comparing vaccination coverage in positive cases of a disease (e.g. influenza) with the vaccination coverage in the population from which the cases are derived (e.g., the same age group). If representative data on cases and vaccination coverage are available, it can provide an inexpensive and ready-to-use method that can be useful in providing early effectiveness estimates or identify changes in effectiveness over time. However, Application of the screening method to monitor influenza vaccine effectiveness among the elderly in Germany (BMC Infect Dis. 2015;15(1):137) emphasises that accurate and age-specific vaccine coverage rates are crucial to provide valid VE estimates. Since adjusting for important confounders and the assessment of product-specific VE is generally not possible, this method should be considered only a supplementary tool for assessing crude VE.

10.2.2.6. Test negative design

The article The test-negative design for estimating influenza vaccine effectiveness (Vaccine 2013;31(17):2165-8) explains the rationale, assumptions and analysis of the test-negative study as applied to influenza VE. Study subjects are all persons who seek care for an acute respiratory illness and influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subject testing negative. This design is less susceptible to bias due to misclassification of infection and the confounding by health care-seeking behaviour, at the cost of difficult-to-test assumptions.

Effectiveness of rotavirus vaccines in preventing cases and hospitalizations due to rotavirus gastroenteritis in Navarre, Spain (Vaccine 2012;30(3):539-43) evaluates effectiveness using a test negative case-control design based on electronic clinical reports. Cases were children with confirmed rotavirus and controls were those who tested negative for rotavirus in all samples. The test-negative design was based on an assumption that the rate of gastroenteritis caused by pathogens other than rotavirus is the same in both vaccinated and unvaccinated persons. This approach may rule out differences in parental attitude when seeking medical care and of physician differences in making decisions about stool sampling or hospitalisation. A limitation is sensitivity of antigen detection which may underestimate vaccine effectiveness. In addition, if virus serotype is not available, it is not possible to study the association between vaccine failure and a possible mismatch of vaccine strains and circulating strains of virus.

10.2.2.7. Case coverage design

10.2.2.8. Impact assessment

A generic study protocol to assess the impact of rotavirus vaccination in EU Member States has been published by the ECDC. It recommends the information that needs to be collected to compare the incidence/proportion of rotavirus cases in the period before and after the introduction of the vaccine. These generic protocols need to be adapted to each country/regions and specific situation.

The impact of vaccination can be quantified in children in the age group targeted for the vaccine (overall effect) or in children of other age groups (indirect effect). The direct effect of a vaccine, however, needs to be defined by the protection it confers given a specific amount of exposure to infection and not just a comparable exposure. Direct and indirect effects in vaccine efficacy and effectiveness (Am J Epidemiol 1991; 133(4):323-31) describes how parameters intended to measure direct effects must be robust and interpretable in the midst of complex indirect effects of vaccine intervention programmes.

First year experience of rotavirus immunisation programme in Finland (Vaccine 2012; 31(1):176-82) estimates the impact of a rotavirus immunisation programme on the total hospital inpatient and outpatient treated acute gastroenteritis burden and on severe rotavirus disease burden during the first year after introduction. The study may be considered as a vaccine-probe-study, where unspecific disease burden prevented by immunisation is assumed to be caused by the agent the vaccine is targeted against.

10.2.2.9. Methods to study waning immunity

The study of vaccine effectiveness against diseases where immunity wanes over time requires consideration of both the within-host dynamics of the pathogen and immune system as well as the associated population-level transmission dynamics. Implications of vaccination and waning immunity (Proc Biol Sci 2009; 276(1664):2071-80) seeks to combine immunological and epidemiological models for measles infection to examine the interplay between disease incidence, waning immunity and boosting.